Cells alter their adhesiveness in response to developmental events and environmental cues. These adaptations are often mediated through integrins, adhesion receptors composed of two transmembrane subunits, .alpha. and .beta. (Hynes, Cell 69:11-25, 1992). Rapid changes in integrin function are critical in cell migration, cellular aggregation, and leukocyte transmigration during inflammation (Hynes, Cell 69:11-25, 1992; Albelda and Buck, FASEB 4:2868-2880, 1990; Hemler, Annu. Rev. Immunol. 8:365-400, 1990; Dustin et al., J. Immunol. 148:2654-2663, 1992; Springer, Nature 346:425-434, 1990; Ginsberg et al., Curr. Opin. Cell Biol. 4:766-771, 1992; Ruoslahti, J. Clin. Invest. 87:1-5, 1991). A given integrin may also manifest varying adhesive competence depending on its cellular environment (Chan and Hemler, J. Cell. Biol. 120:537-543, 1993; Masumoto and Hemler, J. Biol. Chem. 268:228-234, 1993; Weitzman et al., J. Biolo Chem. 268:8651-8657, 1993; Elices and Hemler, Proc. Natl. Acad. Sci. USA 86:9906-9910, 1989; Kirchofer et al., J. Biol. Chem. 265:18525-18530, 1990), or the state of differentiation of the cell in which it is expressed (Haimovich et al., Cell Regulation 2:271-283, 1991; Neugebauer and Reichardt, Nature 350:68-71, 1991; Adams and Watt, Cell 63:425-435, 1990; Chan and Hemler, J. Cell Biol. 120:537-543, 1993). Such variations in function may be due to changes in ligand binding affinity as occurs with certain .beta..sub.3 (Bennett and Vilaire, J. Clin. Invest. 64:1393-1401, 1979), .beta..sub.2 (Altieri et al., J. Cell Biol. 107:1893-1900, 1988), and .beta..sub.1 (Faull et al., J. Cell Biol. 121:155-162, 1993) integrins. Changes in adhesive function may also occur without changes in ligand binding affinity. For example, phorbol esters stimulate the .alpha..sub.5 .beta..sub.1 -dependent adhesion of Chinese Hamster ovary cells (Danilov and Juliano, J. Cell. Biol. 108:1925-1933, 1989) to fibronectin (Fn) with no change in Fn binding affinity. Similarly, certain .beta..sub.3 mutations reduce .alpha..sub.IIb .beta..sub.3 -dependent cell adhesion to fibrinogen (Fg) without changing Fg binding affinity (Ylanne et al., J. Cell Biol. 122:223-233, 1993). Such affinity-independent changes in integrin function are ascribed to "post receptor occupancy events" (Danilov and Juliano, J. Cell. Biol. 108:1925-1933, 1989). Nevertheless, the host cell governs the capacity of solubilized recombinant .alpha..sub.2 .beta..sub.1 to bind to collagen sepharose (Chan and Hemler, J. Cell. Biol. 120:537-543, 1993). This last result suggests that some cell type-specific differences in integrin function may be due to differences in ligand binding affinity.
A variety of in vitro treatments may alter integrin affinity. When purified .alpha..sub.IIb .beta..sub.3 is pretreated with RGD peptides, it subsequently binds Fg and PACl (Duet al., Cell 65:409-416, 1991; Smyth et al., J. Biol. Chem. 267:15568-15577, 1992). Certain anti-.beta..sub.3 antibodies directly increase the Fg binding affinity of .alpha..sub.IIb .beta..sub.3 (Frelinger et al., J. Biol. Chem. 266:17106-17111, 1991) and certain anti-.beta..sub.1 antibodies activate .alpha..sub.5 .beta..sub.1 to bind Fn with high affinity (Faull et al., J. Cell Biolo 121:155-162, 1993). Changes in the divalent cation composition of the extracellular medium, proteolytic digestion, and treatment with reducing agents may also "activate" integrins (Kirchofer et al., J. Biol. Chem. 265:18525-18530, 1990; Gailit and Ruoslahti, J. Biol. Chem. 263:12927-12932, 1988; Altieri, J. Immunol. 147:1891-1898, 1991; Masumoto and Hemler, J. Biol. Chem. 268:228-234, 1993; Weitzman et al., J. Biol. Chem. 268:8651-8657, 1993; Zucker and Nachmias, Arteriosclerosis 5:2-18, 1985; Grant and Zucker, Proc. Soc. Exp. Biol. Med. 165:114-117, 1980). Thus, moieties that interact with the extracellular domain can modulate integrin affinity. Furthermore, lipid environment can alter the ligand binding capacity of an integrin (Smyth et al., J. Biol. Chem. 267:15568-15577, 1992; Conforti et al., J. Biol. Chem. 265:4011-4019, 1990) and an apparently novel lipid, IMF-1, may regulate .alpha..sub.M .beta..sub.2 (Hermanowski-Vosatka et al., Cell 68:341-352, 1992). Although many treatments may change integrin affinity in vitro, the mechanism(s) of physiological modulation has not been defined.